Enomoto, D.N.H.

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Scleroderma: diagnosis and exterimental therapyEnomoto, D.N.H.Publication date2000Link to publicationCitation for published version (APA):Enomoto, D. N. H. (2000). Scleroderma: diagnosis and exterimental therapy. [Thesis, fullyinternal, Universiteit van Amsterdam].General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:06 Jan 2026Chapter 2 Diagnostic features of skin induration: systemic sclerosis, morphea, eosinophilic fasciitis and scleredema. Enomoto DNH, Mekkes JR, Bos JD. Submitted for publication Chapter 2 SUMMARY There are several diseases in which indurated or sclerotic skin is the most important feature. We describe four patients with specific clinical features of systemic sclerosis, morphea, eosinophilic fasciitis and scleredema respectively. These disorders are relatively rare and as such can easily be misidentified. The clinical picture, histology and laboratory manifestations of each disease are described. INTRODUCTION Systemic sclerosis, morphea (localized scleroderma), eosinophilic fasciitis and scleredema share several clinical features which can make it difficult to differentiate between them. Because of the wide range of associated symptoms, patients fall within the scope of many different specialities. A good dermatological examination is helpful, because the proper diagnosis of the abovementioned diseases can be made on the basis of dermatological signs and symptoms. The most important common feature in all conditions is the induration of the skin. Subtle differences in clinical appearance, distribution of the lesions, accompanying symptoms, and serological tests (see Table 1), discriminate between the different entities. Scleroderma (systemic sclerosis and morphea) comprises a spectrum of disorders characterized by induration of the skin and increased collagen deposition in the involved tissues. Eosinophilic fasciitis is recently considered to be a variant of morphea. Scleredema can be considered as a separate entity. It is important to recognize these different disorders because the course and the prognosis of the diseases vary extremely.1 CASE REPORTS Patient 1, a 52-year-old female, noticed swelling and stiffness of both hands. Since two years she complained of symptoms of Raynaud's phenomenon in both hands. Gradually, the skin of hands and face became tight. During the next years the tightness of the skin progressed to the arms, legs and upper part of the trunk. She noticed difficulty with swallowing solid food. At examination, there was sclerodactyly and digital scarring. The skin of the face, arms, legs and chest was shiny and sclerotically indurated (Fig. 1). 64 Diagnostic features of skin induration Figure 1. Shiny sclerotic appearance of the skin in systemic sclerosis. Figure 2. Ivory-white, well demarcated plaque of morphea. 65 Chapter 2 Laboratory investigation revealed the presence of anti-nuclear antibodies and anti-topoisomerase I (Scl-70). Esophagus manometry disclosed dysmotility of the esophagus. Pulmonary function tests showed a carbon monoxide diffusion capacity of 38 % of the predicted value. Biopsy of the skin of her lower arm revealed a mild predominantly lymphocytic infiltrate, around blood vessels and collagen bundles. Patient 2. a 28-year-old man, noticed an indurated white spot on his trunk. Apart from a slight itch, he had no complaints. During the next years he developed several more lesions on his trunk. At examination. Patient 2 had five asymmetrical ivory-white, well demarcated plaques on his trunk (Fig. 2). One was surrounded by erythema, the so-called lilac ring. The plaques were indurated. There were no complaints of Raynaud's phenomenon, the skin of his hands and face was normal. There were no signs of internal involvement. Histopathological examination showed thickened and closely-packed collagen bundles in the dermis. Newly formed collagen had replaced the subcutaneous fat around the sweat glands. Patient 3. a 69-year-old woman, complained of swelling in both legs. Within a few weeks followed by pain and induration of the skin of the legs and the trunk. Another week later she noticed pain and induration of the skin of the forearms. There were no complaints suggestive for Raynaud's phenomenon nor systemic complaints such as shortness of breath or problems with swallowing. At examination, the skin of both hands was normal, there was no digital ulceration. The skin of the arms, legs and trunk had a wood-like induration. The affected skin had a 'peau d'orange' appearance and was reddish-brown (Fig. 3). On the lower arms, the skin directly over the superficial veins showed no induration (groove sign. Fig. 4). Laboratory findings disclosed a raised ESR, 75 mm/h (normal 0-20 mm/h) and an increased number of eosinophils, 1040 x 106/L (normal < 200 x 106/L). Antinuclear antigen, Scl-70 and anti-centromere antibodies were absent. Histological examination of an excisional 'en bloc' biopsy of skin, fascia and muscle taken from the affected skin of the leg revealed a mild inflammatory infiltrate in the dermis, subcutis, fascia and muscle. The infiltrate consisted of lymphocytes, histiocytes and eosinophils. Patient 3 was treated with prednisone 40 mg/day. After 3 months, she noticed a gradual softening of the affected skin. 66 Diagnostic features of skin induration Table 1. Clinical differences between systemic sclerosis, morphea, eosinophilic fasciitis and scleredema Systemic Morphea scleroderma Eosinophilic Scleredema fasciitis Raynaud's phenomenon Sclerodactyly Aspect of the skin Persistent erythema Pigment changes Painful skin lesions ANA Visceral involvement Arthralgias + -diffuse. symmetrical. shiny -+ ---+ --sharply demarcated, ivory-white ~ ± ------woody. orange-brown. peau d'orange --+ -± ± --non-pitting edema -----± 67 Chapter 2 Figure 3. Orange-brown color and peau d'orange appearance of the skin in eosinophilic fasciitis. Patient 4, a 56-year-old man, complained of hardness of the skin of the neck, back and ears. The first symptoms developed 10 years ago. He had insulin-dependent diabetes mellitus since 35 years. He suffered from complications of his diabetes, namely retinopathy and severe angiopathy. The hardness of the skin progressed very slowly, only recently the induration of his skin started to limit the mobility of neck and shoulders. Patient 4 never had Raynaud's phenomenon, and he had no complaints of shortness of breath or problems with swallowing. At examination, the skin of neck, back and ears showed a waxy, non-pitting edema. There was a persistent erythema of the skin of the back (Fig. 5). The skin of the fingers was normal, there was no digital ulceration. There was no atrophy or depigmentation of the skin. There were no abnormal laboratory findings. Pulmonary function and esophagus manometry results were within normal ranges. Biopsy of the skin of the back showed a prominent thickening of the dermis. The collagen bundles appeared to be swollen and were separated from each other by clear spaces. 68 Diagnostic features of skin induration Figure 4. Groove sign in eosinophilic fasciitis Figure 5. Erythema and waxy non-pitting edema of scleredema. 69 Chapter 2 DISCUSSION Systemic sclerosis Scleroderma is a disease of unknown aetiopathogenesis.23 The most striking symptom is the induration of the skin. The skin changes can be divided into three phases.4 The first is edema and swelling of the skin, most often of the hands. The second phase is sclerosis and induration of the affected skin, which gives rise to the distinctive facial features and sclerodactyly. During the third and last phase there is atrophy of the skin. The sclerosis of the skin almost always starts at the hands and face and slowly progresses to the proximal parts of the body.5 The skin indurations are symmetrical, and pigment changes are often observed. The skin has a shiny appearance. Scleroderma has a distinct histological picture. During the typical sclerotic phase, the dermis is thickened because of an increased number of compact collagen bundles. The epidermal appendages are obliterated or tightly packed in homogeneous collagen. As a rule, there are no mucin deposits in the dermis. The onset of systemic sclerosis is often preceded by Raynaud's phenomenon.6 The fingertips of these patients characteristically show scars and ulcerations. The extent of visceral involvement due to sclerosis (fibrosis) of the affected organs is a major prognostic factor. Recently, patients with systemic sclerosis were subdivided into two major groups, limited cutaneous sclerosis and diffuse cutaneous sclerosis.7 The first group has skin induration limited to the face and forearms, there is usually a long history of Raynaud' s phenomenon. Involvement of the viscera is usually restricted to the esophagus. The course of limited systemic sclerosis is usually benign. Diffuse systemic sclerosis belongs to the rapidly progressive end of the spectrum. Patients have widespread sclerosis of the skin, and more importantly regarding the prognosis of the disease, extensive involvement of their internal organs. Morphea (en plaque, linear morphea and generalised morphea) On histological grounds, no distinction can be made between systemic sclerosis and morphea (localized scleroderma). On clinical grounds this distinction can readily be made.8910 Patients with morphea often have one or more sharply demarcated indurated maculae or plaques on the trunk. The lesions vary from 1-30 centimeter and have a shiny, waxy and ivory-white appearance. Sclerotic plaques of recent onset are surrounded by a purple-red ring (lilac ring). The skin lesions are never painful and mostly asymmetrical. They appear predominantly on the trunk, sometimes the extremities are involved. The hands and especially the fingertips are never involved and appear completely normal. Patients never complain of symptoms of Raynaud's phenomenon, and there is 70 Diagnostic features of skin induration no visceral involvement. These last two features are very important in distinguishing between systemic sclerosis and generalised morphea. Spontaneous remission of the skin abnormalities often occurs, although (post inflammatory) hyperpigmentation may persist for years. There are no laboratory abnormalities. Linear morphea is a specific form of this entity, it consists of a linear, band-shaped lesion. This induration is asymmetrical and usually located on one of the extremities. Sometimes it causes atrophy of the underlying muscles, and normal growth of the bones may become impaired. If these anomalies occur at a young age, severe disfigurement may be the result. Eosinofilic fasciitis ( Shulman's disease)." This disease is characterized by rapidly progressive and painful swelling of one or more extremities.1213 Within a few days to weeks followed by a orange-brown, woody induration of the involved skin. Very distinctive is the 'peau d'orange' aspect of the indurated skin. Often the so-called groove sign can be observed; this is the absence of fibrosis over the superficial veins. Eosinophilic fasciitis can be distinguished from systemic sclerosis by the above described clinical picture. Patients with this disease also show no sign of nailbed changes nor is there any evidence of Raynaud's phenomenon. The skin of the face and the hands is not involved, this is a major distinguishing feature of eosinophilic fasciitis compared to systemic sclerosis. There is often eosinophilia in the peripheral blood; a normal number of eosinophils does not rule out the diagnosis eosinophilic fasciitis. Antinuclear antibodies are absent. An excisional biopsy including fascia and muscle can be diagnostic. Typically, an infiltrate containing lymphocytes, histiocytes and eosinophils is found around the fascia and in the subcutis. Contractures of the joints are often seen. Synovitis and a symmetrical polyarthritis can develop. This disease is often preceded by a carpal tunnel syndrome.1' Some patients react favourable on high dose steroids. Scleredema (Buschke or diabeticorum) Scleredema is a very rare collagen disorder.15 The skin of the upper part of the back, the neck and the shoulders is most frequently involved. There are two types of scleredema, namely scleredema of Buschke16 (adultorum), and scleredema diabeticorum.17 The first is usually preceded by a febrile illness and regarded as a post-infectious condition. Scleredema diabeticorum is found in longstanding and often unsatisfactorily controlled diabetes. Scleredema of Buschke starts often after a streptococcal infection. Days to weeks after the infection, a rapidly progressive, symmetrical and painless non-pitting induration of the skin of neck, back and shoulders is observed. Hands 71 Chapter 2 and feet are seldom or never involved. A non-persistent erythema can be found. The non-pitting induration can resolve spontaneously in 6 to 24 months. Occasionally, these skin lesions persist for years. The skin shows no atrophy or pigment changes. There is no visceral involvement. No specific laboratory or immunological abnormalities have been noticed. In contrast, the histology is very specific, the epidermis is normal, the dermis is prominently thickened. This thickening is caused by swollen collagen bundles. These collagen bundles are separated from each other by clear spaces (fenestrations) which contain acid mucopolysaccharides. Scleredema diabeticorum shares the same clinical and histological features with exception of the infectious phase. The onset of the skin indurations is more gradually. The erythema is more often observed and seems to be persistent. Patients suffer almost always of complications of their disease, such as retinopathy, neuropathy or vascular problems. Better control of the diabetes mellitus has no effect on the clearing of the skin indurations. In contrast to scleredema of Buschke, spontaneous regression of the skin tightness is seldom seen. Other authors18 proposed a subdivision into 3 groups. The first group the classical one as described by Buschke with a preceding febrile illness and spontaneous resolution. The second group are those patients who presented with scleredema but without a preceding febrile illness. These patients showed no spontaneous improvement. The third group are the patients with long-standing and poorly controlled diabetes with complications of their disease, especially vascular problems. The name scleredema adultorum is a misnomer, it was introduced to distinguish this entity from scleredema neonatorum. Many children have been described with clinical features of scleredema (of Buschke), therefore the term scleredema is more suitable. Scleredema has been associated with paraproteinemia and multiple myeloma.1920 CONCLUSION In summary, sclerosis of the skin is not always scleroderma. A good knowledge of the different clinical presentations of systemic sclerosis, morphea, eosinophilic fasciitis and scleredema is necessary to discriminate between these closely resembling entities. Because the prognosis and therapeutic approach of each condition is completely different, it is important to make the proper diagnosis in an early stage of the disease. 72 Diagnostic features of skin induration REFERENCES 1. Jablonska S, Blaszcyk M. Scleroderma-like disorders. Seminars Cutaneous Med Surg 1998;17:65-76. 2. Black CM. The Aetiopathogenesis of systemic sclerosis. J Int Med 1993; 234: 3-8. 3. Carwile LeRoy E. A brief overview of the pathogenesis of scleroderma (systemic sclerosis). Annals Rheum Dis 1992;51:286-288. 4. Silver RM. Clinical aspects of systemic sclerosis (scleroderma). Annals Rheum Dis 1991;50:854-861. 5. Perez Ml, Kohn SR. Systemic sclerosis. J Am Acad Dermatol 1993; 28: 525-547. 6. Belch JF. Raynaud's phenomenon: its relevance to scleroderma. Annals Rheum Dis 1991;50:839-845. 7. LeRoy. Black C, Fleischmajer R et al. Scleroderma (systemic sclerosis): Classification, Subsets and Pathogenesis. J Rheumatol 1988;15:202-205. 8. Peterson LS, Nelson AM, Su WPD. Classification of Morphea (localized scleroderma). Mayo Clin Proc 1995;70:1068-1076. 9. Nelson AM. Localized scleroderma including morphea, linear scleroderma and eosinophilic fasciitis. Curr Probl Pediatr 1996;26:317-323. 10. Falanga V. Localized scleroderma. Med Clin North Am 1989:73:1 143-1 156. 11. Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol 1974; 1 (suppl):46. 12. Moore TL, Zuckner J. Eosinophilic fasciitis. Seminars Arthitis Rheumatism 1980;9:228-235. 13. Maddison PJ. Eosinophilic fasciitis. British J Rheumatol 1990;29:81-83. 14. Doyle J. Eosinophilic fasciitis: extracutaneous manifestations and associations. Cutis 1984;34:259-261. 15. Venencie PY, Powell FC, Su WPD et al. Scleredema: a review of thirty-three cases. J Am Acad Dermatol 1984; 11:128-134. 16. Carrington PR, Sanusi ID. Winder PR et al. Scleredema adultorum. Review. Int J Dermatol 1984;23:514-522. 17. Cohn BA, Wheeler CE, Briggaman RA. Scleredema adultorum of Buschke and Diabetes Mellitus. Arch Derm 1970;101:27-35. 18. Graff R. Discussion of scleredema adultorum. Arch Dermatol 1968;98:319-320. 19. Oikarinen A, Ala-Kokko L, Palatsi R et al. Scleredema and paraproteinemia. Arch Dermatol 1987;123:226-229. 20. Salisbury JA, Shallcross H, Leigh IM. Scleredema of Buschke associated with multiple myeloma. Clin Exp Dermatol 1988:13:269-270. 73 74 

Scleroderma: diagnosis and exterimental therapy

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Scleroderma: diagnosis and exterimental therapy

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